The invention concerns a method for the production and filling of an application package for a liquid pharmaceutical product, and involves a thermoforming method using a thermoforming film comprised of plastic. This produces an application package that is configured as a blister pack, i.e. with an essentially flat back side covered by a covering film and a usually translucent or transparent front side comprised of a thermoforming film molded part.
In a method of the present type, a thermoforming film comprised of thermoplastics laminated together is first heated in order to plasticize the thermoforming film at least in partial areas. After heating, the thermoforming film is positioned over a mold, and the plasticized thermoforming film is formed into thermoforming dies configured as recesses in the mold, i.e. thermoformed into said dies using a vacuum and/or blast air. For this purpose, in a method of the present type, a mold is used that forms a molded part having a chamber for the liquid pharmaceutical product and a tube-shaped application duct that opens into said chamber by means of thermoforming of the thermoforming film. The chamber and the application duct are enclosed by a non-thermoformed, essentially flat bonding area of the thermoforming film.
The liquid pharmaceutical product is filled into the thermoforming film that has been molded into a plastic molded part in this manner, the chamber and application duct thereof first being open at the top, with said liquid product essentially filling the chamber, and depending on the filling level, the application duct as well.
The thermoformed and filled thermoforming film is then covered with an essentially flat covering film in order to seal the chamber and the application duct, thus forming a pipet-shaped structure in the form of a blister pack. When it is opened, this blister pack becomes a pipet in the area of a tip of the application duct for applying the pharmaceutical product contained therein, giving rise to the double function of the present application package: it functions as a package for the liquid pharmaceutical product on the one hand and a pipet for application thereof on the other.
In order to complete the application package, the covering film is finally bonded to the bonding area of the thermoforming film enclosing the chamber and the application duct. Depending on the pharmaceutical product with which the application package is to be filled, bonding of the covering film to the thermoforming film is definitely a critical process step, as this bonding must be liquid- and vapor-tight, and generally diffusion-tight as well, and the long-term permeation properties of the liquid pharmaceutical product must also be taken into account.
The main field of use of an application package produced by the method according to the invention is the storage and application of pharmaceutical products active against parasites in pets, particularly fleas and ticks in dogs and cats. Such antiparasitics used in veterinary medicine often contain as their active agent fipronil, which is to be applied directly to a pet's skin in liquid form dissolved in ethanol and/or other organic solvents. The application package is therefore configured as a pipet having a particularly long, tube-shaped extraction duct in order to ensure that the active agent can be applied to the skin even through the fur of a long-haired pet. An active agent solution that cannot penetrate to the skin of the pet because it is absorbed by the pet's fur cannot achieve the desired effect.
However, it is particularly difficult to apply a liquid active pharmaceutical agent to the skin of a dog or cat, as animals generally do not hold still or sometimes move unexpectedly, so that the liquid active agent solution is all too easily spilled or absorbed by the animal's fur and fails to reach the skin. The tube-shaped application duct, i.e. the pipet shaft, must therefore in this application not only be particularly long, but must also have an exceptionally small cross-section so that the solution contained in the chamber of the application package is only discharged from the open-tipped application duct when pressure is applied to the chamber. The active agent solution therefore must not leak from the open application duct unless pressure is applied to the chamber, even when the application duct is held with the opening facing down.
Finally, a further problem is that a liquid preparation containing the active agent fipronil is not compatible with every plastic, but requires special thermoforming films and covering films comprised of plastic films laminated together which must comprise a layer of an acrylonitrile/methyl acrylate (AMA) copolymer available on the market under the registered trademark Barex®. Although such films can be thermoformed and sealed, their thickness sometimes varies, particularly when the film is plasticized for thermoforming and then deformed.
In the case of active agent solutions containing fipronil, which often contain further solvents in addition to ethanol, such as butyl hydroxyanisole and butyl hydroxytoluene, and show particularly high penetration capacity, the variations in thickness occurring in particular in AMA copolymer films and laminates containing them cause problems with tight bonding of the covering film to the bonding area of the thermoforming film enclosing the chamber and the application duct. The slightest irregularity in the bond between the covering film and the thermoforming film can cause the active agent solution to leak or diffuse out during longer-term storage of the application package filled with said active agent solutions. This problem scenario is exacerbated by the fact that with the present application package, active agent solution is supposed to emerge from the applying duct, opened at the tip, only when pressure is exerted on the chamber. Administration on a pet, specifically, frequently entails a high pressure being exerted on the chamber, it being difficult to hold the pet still. In such situations the active agent solution is nevertheless supposed to emerge only through the opened application duct.